The crystal structure of the DNA complex of a STAT-1 homodimer has been determined at 2.9 [unreadable] resolution. STAT-1 utilizes a DNA binding domain with an immunoglobulin fold, similar to that of NFkB and the p53 tumor suppressor protein. The STAT-1 dimer forms a contiguous C-shaped clamp around DNA that is stabilized by reciprocal and highly specific interactions between the SH2 domain of one monomer and the C-terminal segment, phosphorylated on tyrosine, of the other. The phosphotyrosine binding site of the SH2 domain in each monomer is coupled structurally to the DNA binding domain, suggesting a potential role for the SH2-phosphotyrosine interaction in the stabilization of DNA interacting elements.